It is known that some beta-lactam acylated with D-2-phenylglycine are valuable pharmaceutically active compounds. Thus 6-amino-penicillanic acid acylated with D-2-phenylglycine is ampicillin and 7-amino-3-desacetoxy-cephalosporanic acid acylated with the above amino acid is also known as a semi-synthetic antibiotic called Cefalexin.
The above and similar synthetic antibiotics can be preferably prepared from D-2-phenylglycine by forming a potassium salt of N-(1-methyl-2-methoxy-carbonyl-vinyl)-D-2-phenylglycine or the potassium salt of N-(1-methyl-2-ethoxy-carbonyl-vinyl)-D-2-phenylglycine and preparing a mixed anhydride from the above compound and reacting same with a corresponding beta-lactam without isolation.
The enamine-salt prepared from D-2-phenylglycine was first prepared by Elizabeth Dane et al. [Chem. Ber. 98. 789-796 (1965)]. According to the process D-2-phenylglycine is boiled with the ethyl ester of acetoacetic acid and with potassium hydroxide and the product precipitating upon cooling is recrystallized from ethanol. Yield: 81.5%. The obtained product contains a half mole of crystal water which has to be removed before working up. According to Czechoslovakian patent application No. 147,194 the above reaction is carried out in ethanol. Yield: 75%.
The products obtained according to the above processes can be worked up according to Hungarian Patent 155,099 or German Patent 3,012,669.
It is also known that the acylated derivatives of 6-amino-penicillanic acid and 7-amino-cephalosporanic acid can be used in therapy as antibiotics of wide spectrum. One preferred representative of said compounds is D[(-)-.alpha.-amino-(para-hydroxy-phenyl)-acetamido)]penicillanic acid (referred to hereinafter as amoxicillin).
The criteria which amoxicillin has to meet are disclosed at pages 3-4. Of the British Pharmacopoea 1973. One important criterium is the optical rotation of the product which is determined in the Pharmacopoea as: (.alpha.).sub.20.sup.D =(+290.degree.)-(+310.degree.) (C=0.2% by weight/volume, water). Amoxicillin can be prepared from 6-amino-penicillanic acid or salt thereof and from a derivative of para-hydroxyphenylglycine according to British Patent 978,178. According to British Patent 1,339,605 6-amino-penicillanic acid is used in the form of its silylated derivative and the silyl group is removed after reaction. According to U.S. Pat. No. 3,674,776 the para-hydroxyphenylglycine derivative containing a protected amino-group is reacted with 6-amino-penicillanic acid or a salt thereof.
In the above patents the mixed anhydrides of .beta.-keto-esters formed by condensation of alkyl esters of acetoacetic are mentioned as preferred out of the reactive derivatives formed on the amino group. The preparation of said compounds can be performed by a reaction of para-hydroxy-phenylglycine with an alkali hydroxide, by separation of the formed alkali salts by reacting with an alkyl ester of acetoacetic acid and conversion of the enamine to a mixed anhydride, preferably with chloroformic acid esters. The disadvantage of the process is that the purity of Amoxicillin prepared from a mixed anhydride obtained like this does not achieve the requirements of the Pharmacopoea. The optical rotation of Amoxicillin prepared according to the Examples of U.S. Pat. No. 3,674,776 is only (.alpha.).sub.D.sup.20 =+246.5.degree. (c=0.1% in water). Purity of Amoxicillin in Example 1 of British Patent 1,339,605 is 80% by weight.
It is also known the Dane-salt was also prepared from para-hydroxyphenylglycine in methanol at the boiling point of the reaction mixture using an ester of acetoacetic acid and replacing the mixture by toluene at the end of the reaction and by crystallizing the product from toluene. This method using toluene can not be reproduced in industry because by increasing the size the mixture contains more and more unreacted alkali salt of amino acid and cannot be filtered.
In order to eliminate partially the above problems it has been suggested to add a lye to the system when preparing the Dane-salt (Hungarian Patent 182,519) or to use isopropanol as an alkanol (Hungarian Patent 186,143) by maintaining a narrow temperature range (65.degree.-70.degree. C.).
At a temperature higher than this a reesterification takes place. The above processes did not yield the desired improvement on industrial scale.
In each further step the mixed anhydride was formed with a chlorocarbonic acid ester forming an acylating agent.
The mixed anhydrides formed from the Dane-salt and chlorocarbonic ester can be well used for peptide chemical synthesis, but the preparation thereof is not without problems. Thus they can be prepared only at very low temperature (about -20.degree. C.) and when using the very toxic chlorocarbonic esters under industrial conditions great care has to be paid and the costs are high.